The present invention relates to new bis-platinum complexes in which two platinum cores are connected by a polyamine ligand and to pharmaceutical compositions containing them.
The use of platinum complexes in cancer chemotherapy is well known. Cisplatin (CDDP) for example is used in therapy to treat testicular, ovarian, head and neck and small cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumor becoming refractory to treatment by the agent.
To overcome the nephrotoxic effects of cisplatin, a second-generation analogue, carboplatin, was developed. Carboplatin, or [Pt(NH.sub.3).sub.2 (CBDCA)] (where CBDCA stands for 1,1'-cyclobutanedicarboxylate), is clinically effective against the same spectrum of carcinomas as cisplatin, but exhibits a reduction in the nephrotoxic effects.
A number of different mono- and bis-platinum complexes have been prepared in an attempt to treat different tumors or carcinomas (U.S. Pat. No. 4,225,529; U.S. Pat. Nos. 4,250,189; 4,553,502; U.S. Pat. No. 4,565,884). None of such compounds is currently used in therapy.
More recently, new bis-platinum(II) complexes are disclosed (U.S. Pat. No. 4,797,393), which have a bridging diamine or polyamine ligand and primary or secondary amines or pyridine type nitrogen-carrying ligands attached to the platinum complex, as well as two different or identical ligands which may be a halide, sulphate, phosphate, nitrate, carboxylate, substituted carboxylate or dicarboxylate. The expert technician will appreciate that the complex is neutral, since two anions counter-balance the +2 charge on each platinum core.
WO 91/03482 further discloses bis-platinum(II) complexes such as those described in U.S. Pat. No. 4,797,393, the main difference consisting in having two nitrogen-carrying neutral ligands and only one charged ligand on each platinum core. This results in a complex having a +2 total charge. These complexes interfere with DNA replication forming interstrand cross-links, which cause conformational changes on the DNA and eventually lead to the inhibition of replication and to the final cytotoxic effect.
Polyamine bridging ligands are generally mentioned as possible ligands in such complexes, but not example is given.
Even if such compounds are able to partially overcome the resistance to cisplatin in cisplatin-resistant cell lines and thus may have a broader spectrum of activity than cisplatin, nevertheless their collateral sensitivity appears lower when compared with cisplatin (see Table I).
On the other hand, polyamines are considered essential in cell proliferation. The naturally occurring polyamines in mammalian cells are putrescine, spermidine and spermine. A wide variety of related amines are found in other organisms and may play critical roles in their physiology. Nevertheless, it is also known that the association of cationic polyamines with negatively charged DNA induces significant structural changes in DNA. Spermidine and spermine can cause DNA to condense and aggregate and induce reversible B-to-Z transition in certain DNA sequences (Marton, L. J. et al., Annu. Rev. Pharmacol. Toxicol., 1995, 35: 55-91). This led the researchers to focus their attention on the potential use of polyamines as antitumor drugs (Basu, H. S. et al., Biochem. J., 1990, 269: 329-334; Yanlong Li et al., J. Med. Chem., 1996, 39: 339-341).
Mono-platinum complexes with spermine are described in J. Clin. Hematol. Oncol., 7(1), 322-9 (1977) and Proc. Int. Congr. Chemother. 13th, 17, 286/100-286/102 (1983), but in both the cases chelates with spermine are obtained. In the first mentioned paper in particular it is described a complex in which the spermine coordinates the whole coordination sphere of the platinum(II) core.
Mono-platinum complexes with polyamines are also disclosed in Can. J. Chem., 72, 1225-9 (1994), but, even if no structure is showed, it can be inferred that they are again chelates.
J. Inorganic Biochem., 53, 177-190 (1994) discloses triplatinum complexes linked by two spermidine molecules. Again the external platinum moieties are involved in a chelating ligand with two spermidine nitrogen atoms.
It can be understood that using polyamines as such in the complex formation it is not possible to avoid that two or more nitrogen atoms be involved in a chelate formation with the platinum coordination sphere.
We have now found that a selected number of bis-platinum(II) complexes of WO 91/03482 having a polyamine bridging ligand are particularly active against both resistant and non-resistant cell lines.